Xue Xuling, Zhu Chengcheng, Chen Huachao, Bai Yang, Shi Xiangchao, Jiao Yang, Chen Zhongyan, Miao Yupeng, He Weijiang, Guo Zijian
State Key Laboratory of Coordination Chemistry, Coordination Chemistry Institute, School of Chemistry and Chemical Engineering, Nanjing University , Nanjing 210093, P. R. China.
Inorg Chem. 2017 Apr 3;56(7):3754-3762. doi: 10.1021/acs.inorgchem.6b02148. Epub 2016 Dec 6.
Sensitizing the antitumor activity of monofunctional Pt complexes is a reliable approach to developing antitumor agents different from the classic Pt-based drugs. Considering the poor intracellular accumulation of monofunctional Pt complexes, in this study, the photosensitizing monofunctional Pt complex Pt-BA was derived from a weak BODIPY (boron-dipyrromethene)-derived photosensitizer BA, with the purpose to improve its antitumor cytotoxicity via enhancing its intracellular accumulation with a short time photo-irradiation. Photoinduced reactive oxygen species (ROS) determination indicated that the Pt center in Pt-BA is able to improve the photoinduced ROS production ability of BA, which makes Pt-BA a mild photosensitizer. Fluorescence imaging disclosed that dark incubation makes Pt-BA accumulate mainly on the surface of cell membrane, and the later short time photo-irradiation (5 min) promotes distinctly the intracellular accumulation of Pt-BA, which has been confirmed by inductively coupled plasma-mass spectrometry determination. Flow cytometric Annexin V-FITC assay indicated that the short time irradiation of Pt-BA induces in situ the cell membrane damage, which might finally enhance the intracellular accumulation of this monofunctional complex. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay confirmed that the short time photo-irradiation promotes distinctly the antitumor cytotoxicity of Pt-BA against MCF-7, SGC-7901, A549, and HeLa cell lines. The photopromoted antitumor activity of Pt-BA implies that modifying monofunctional Pt complex as a mild photosensitizer to promote its cell accumulation is a useful approach to sensitizing the antitumor activity of monofunctional Pt complex and renders the possibility of monofunctional Pt prodrugs for precise chemotherapy via only short time photoactivation.
使单功能铂配合物的抗肿瘤活性敏感化是开发不同于经典铂类药物的抗肿瘤药物的可靠方法。考虑到单功能铂配合物在细胞内的积累较差，在本研究中，光敏单功能铂配合物Pt-BA源自一种弱的硼二吡咯亚甲基（BODIPY）衍生的光敏剂BA，目的是通过短时光照增强其细胞内积累来提高其抗肿瘤细胞毒性。光诱导活性氧（ROS）测定表明，Pt-BA中的铂中心能够提高BA的光诱导ROS产生能力，这使得Pt-BA成为一种温和的光敏剂。荧光成像显示，黑暗孵育使Pt-BA主要积聚在细胞膜表面，随后的短时光照（5分钟）明显促进了Pt-BA的细胞内积累，这已通过电感耦合等离子体质谱测定得到证实。流式细胞术Annexin V-FITC分析表明，Pt-BA的短时光照原位诱导细胞膜损伤，这最终可能增强这种单功能配合物的细胞内积累。3-（4,5-二甲基噻唑-2-基）-2,5-二苯基四氮唑溴盐分析证实，短时光照明显促进了Pt-BA对MCF-7、SGC-7901、A549和HeLa细胞系的抗肿瘤细胞毒性。Pt-BA的光促进抗肿瘤活性表明，将单功能铂配合物修饰为温和的光敏剂以促进其细胞积累是使单功能铂配合物的抗肿瘤活性敏感化的有用方法，并使得单功能铂前药仅通过短时光激活进行精确化疗成为可能。
